tbuckley/cabot-search huggingface dataset:
Abstract 5989: Brain metastasis mouse models for the evaluation of multikine inhibitors on ROS1-fusion-positive lung cancer
Authors: Hui Qi, Xia Xiong, Huanhuan Liu, Yuying Yang, Chunlei Dai, Haoxia Zhao, Bingrui Han, Xuzhen Tang, Qunsheng Ji
Journal: Cancer Research (2022)

Abstract Lung cancer is the leading cause of cancer-related death worldwide. Nearly 80% of lung cancers are non-small cell lung cancer (NSCLC) and 60% of them are diagnosed at the metastatic stage. Brain metastases affect more than 20% of NSCLC patients with poor prognosis and disabling symptoms. However, few therapies have been approved for the treatment of lung cancer brain metastases. A panel of rapid, predictive and clinically-relevant animal models are urgently needed to study the biology of brain metastases and to identify effective therapeutic approaches.Considering both progression and treatment of lung cancer brain metastases will be limited by the blood-brain barrier (BBB), here we describe methods for efficient establishment of brain metastases mouse models via different injection route (intracranial, intracardiac or intracarotid), to identify a model that permits tumor cell growth in the unique brain microenvironment without compromising BBB. Meanwhile, we established a novel ROS1 positive patient-derived xenograft (PDX) model together with its PDC sub-line, in which the exon 2 of SDC4 was fused to the exon 32 of ROS1 (SDC4ex2-ROS1ex32). The cell has been transduced with firefly luciferase expression vector for in vivo imaging detection. Three ROS1 inhibitors were tested on these brain metastasis and subcutaneous models to compare their efficacies. In summary, we established brain metastases lung cancer PDX models as reliable platforms for interrogation of targets and kinetics related mechanism and for drug screening. The use of such techniques will increase our knowledge of the metastatic process and help identify new targets of cancer metastasis. Citation Format: Hui Qi, Xia Xiong, Huanhuan Liu, Yuying Yang, Chunlei Dai, Haoxia Zhao, Bingrui Han, Xuzhen Tang, Qunsheng Ji. Brain metastasis mouse models for the evaluation of multikine inhibitors on ROS1-fusion-positive lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5989.
Abstract 5452: Discovery of a novel seleno-leonurine analog as a potential therapeutic for ovarian cancer
Authors: Asif Raza, Jacek Krzeminski, Shantu Amin, Arun Sharma
Journal: Cancer Research (2022)

Abstract Leonurine is an active alkaloid that is extracted from Traditional Chinese Medicine Herba leonuri. It has been reported to be beneficial for cardiovascular diseases, including atherosclerosis, acute and chronic myocardial infarction (MI), and ischemic stroke. Mao et al. illustrated that leonurine could up-regulate the expression of phosphorylated p38 and down-regulate phosphorylated Akt expression through inhibiting mitochondrial pathway, thus suppressing the proliferation and promoting lung cancer cell apoptosis. Accumulating evidence suggest that the extract of Leonurus sibiricus transgenic roots could induce apoptosis in different grades of human glioma cells and significantly promotes cisplatin sensitivity in cervical cancer cells via repressing cell proliferation, improving intrinsic cell apoptosis and inhibiting the expression of P-Gp and MRP1 protein, which has potential therapeutic value in cervical cancer treatment. In the present study, we designed and synthesized several selenium analogs of leonurine and their cytotoxicity were assessed using four different ovarian cancer cell lines viz. OVCAR-3, OVCAR-10, ES2, and drug resistant HeyA8 cells. Compared to the control and leonurine group, compound 834 inhibited the ovarian cancer cell viability in dose- and time-dependent manner. The IC50 values of compound 834 was 4.6 µM, 3.8 µM, 6.2 µM, and 5.7 µM for OVCAR-3, HeyA8, OVCAR-10, and ES2 cells, respectively, while for leonurine the IC50 value was &amp;gt;500 µM for 48 h treatment. To further acquaint the effect of 48 h treatment on cell proliferation, we performed trypan blue cell viability assay, trypan blue dye exclusion assay, Annexin V/7-AAD, Caspase 3/7 apoptosis assays and Western blotting of apoptotic proteins involved in apoptosis. Compound 834 significantly induced apoptosis in OVCAR-3 and HeyA8 cells in dose dependent manner. Upregulation of several apoptotic proteins, as evident by Western blot, suggested that 834 causes induction of apoptotic pathways efficiently. Further, the cell cycle analysis showed a significant arrest of OVCAR-3 and HeyA8 cells in the S-phase, which was further confirmed by the analysis of cyclin A2, cyclin-E1, p21 and p27 proteins expression. Conclusively, our research revealed that leonurine analog 834 significantly induces apoptosis in ovarian cancer cells via repressing cell proliferation, improving intrinsic cell apoptosis and inhibiting the expression of several signaling proteins, which has potential therapeutic value in ovarian cancer treatment. Citation Format: Asif Raza, Jacek Krzeminski, Shantu Amin, Arun Sharma. Discovery of a novel seleno-leonurine analog as a potential therapeutic for ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5452.
Abstract 3724: <i>PBRM1</i> loss in RCC: Implications for immunotherapy
Authors: Alexander Metz, Rahmat Sikder, Moataz Ellithi, Micheal Slifker, Philip Abbosh
Journal: Cancer Research (2022)

Abstract Introduction The association between mutational status of the polybromo-1 (PBRM1) gene in clear cell renal cell carcinomas (ccRCCs) and papillary RCCs (pRCCs) in the response to immune checkpoint blockade is debatable. Here, we aim to characterize the biological changes that PBRM1 loss causes and how these changes might modulate the immune response to cancer. Methods and Results Gene set enrichment analysis (GSEA) of PBRM1-mutant RCC tumors from TCGA data sets reveals NF-kB signaling via TNFα, hypoxia, and p53 signaling pathways are enriched compared to PBRM1 WT. PBRM1-mutant tumors also have increased number of insertion/deletion mutations and non-synonymous mutations that are directly proportional to neoantigen burden. CIBERSORT analysis of PBRM1-mutant ccRCC tumors reveals decreased transcriptional signature associated with CD8+ T-cell infiltration and lower levels of two cytolytic signatures. PBRM1-mutant ccRCC cell lines have constitutively activated NF-kB signaling, as well as a greater induction of NF-kB in response to TNFα via western blot when compared with PBRM1 reconstituted cells. Additionally, PD-L1 is more strongly expressed on the cell surface of PBRM1-mutant cells, which may modulate their interactions with the immune system. However, MHC-I expression was not found to be significantly different between PBRM1 mutant and reconstituted cells. Conclusions These results shed light on changes in biology and immunogenicity associated with or caused by PBRM1 loss. They also implicate NF-kB as a potential moderator of immune response, which should be studied further to characterize its effects on immune checkpoint blockade therapy (ICB). Citation Format: Alexander Metz, Rahmat Sikder, Moataz Ellithi, Micheal Slifker, Philip Abbosh. PBRM1 loss in RCC: Implications for immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3724.
Resurgence of Sexually Transmitted Diseases in the US
Authors: Bridget M. Kuehn
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Fueling the fire in the gut
Authors: Chia-Hao Lin, Li-Fan Lu
Journal: The Journal of Experimental Medicine (2022)

Gut dysbiosis has long been associated with the development of Crohn’s disease and other gastrointestinal disorders. Otake-Kasamoto et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20211291) report that dysbiotic microbiota-derived bioactive lipids, lysophosphatidylserines, can promote pathological Th1 cell responses through inducing metabolic reprogramming and epigenetic changes.
Abstract 3495: A novel Mediterranean dietary intervention for prostate cancer
Authors: Samuel Cass, Jennifer Wargo, Curtis Pettaway, Louis Pisters, John Davis, Brian Chapin, John Ward, Carrie Daniel, Justin Gregg
Journal: Cancer Research (2022)

Abstract Active surveillance (AS) is a safe management strategy for men with low-risk prostate cancer; however, nearly 35% of men on AS will undergo definitive treatment within 4 years, most commonly due to disease progression. Determining a non-invasive means of limiting disease progression would allow men to avoid quality of life issues associated with radical prostate treatment. Some modifiable factors, such as obesity and lipid levels, are associated with prostate cancer risk, though no behavioral intervention has been shown to affect prostate cancer outcomes. Using a prospective study of men on active surveillance, our group recently demonstrated that higher quality diets were associated with a significantly lower risk of disease progression. The Mediterranean diet (MD) specifically may be beneficial for men with localized prostate cancer (PCa) on active surveillance (AS) because of its anti-inflammatory, antilipidemic, and chemopreventive properties. Furthermore, recent evidence supports that dietary interventions can induce modulation of the gut microbiome, and consequently, immune function and inflammatory pathways, which warrants further investigation of the microbiome’s role in the context of prostate cancer. Here, we describe a novel dietary intervention among a group of men with localized prostate cancer who are electing to undergo prostatectomy for prostate cancer treatment. The intervention is a feeding study involving the provision of an isocaloric, high quality diet based on the lipid-lowering and anti-inflammatory parameters of the Mediterranean diet, including a strong focus on fiber-rich plant foods and healthy sources of mono and poly-unsaturated fatty acids. The primary outcome in this pilot study is the feasibility of a neoadjuvant dietary intervention. Secondary outcomes include studying the effects of the diet on metabolic parameters, the fecal microbiome, and changes in circulating metabolites shown to be associated with progression on active surveillance. Furthermore, by focusing on African-American and non-Hispanic White males, this study may provide insights into the key differences in inflammatory, immune and microbiome signatures, which may underly the prominent cancer-racial disparity seen in African-American men. Therefore, this study will gain preliminary data needed to inform further dietary interventions that may impact risk of progression in select men with prostate cancer enrolled on active surveillance. Citation Format: Samuel Cass, Jennifer Wargo, Curtis Pettaway, Louis Pisters, John Davis, Brian Chapin, John Ward, Carrie Daniel, Justin Gregg. A novel Mediterranean dietary intervention for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3495.
Abstract 912: A novel genetically engineered H3.3G34R model reveals cooperation with ATRX loss in upregulation of PRC2 target genes
Authors: Aalaa Abdallah, Herminio J. Cardona, David J. Picketts, Daniel J. Brat, Xiao-Nan Li, Oren J. Becher
Journal: Cancer Research (2022)

Abstract Pediatric High Grade Glioma (pHGG) is a collection of molecularly distinct subtypes with different prognoses depending on the genetic drivers. One particularly aggressive subtype is H3.3G34R mutant gliomas, which are currently incurable and in need of improved therapies. Interestingly, H3.3G34R mutant gliomas commonly harbor TP53mutations, ATRX mutations, and alterations in PDGFRA signaling. The mechanism by which H3.3G34R promotes gliomagenesis is still somewhat unclear and additional models are needed to dissect its role in tumorigenesis. We used the RCAS Tv-a system to model H3.3G34R pHGG in mice. Nestin expressing progenitors in the frontal cortex of Nestin-Tva (Ntva); p53 fl/fl; ATRX fl/fl or Ntva; p53 fl/fl mice were infected with H3.3G34R or H3.3WT, PDGFA, and Cre, and monitored for signs and symptoms of tumor formation. RNAseq analysis and immunophenotype were used to characterize the tumors. We observed that H3.3G34R did not significantly impact tumor latency independent of ATRX status. ATRX loss significantly increased tumor latency independent of H3.3G34R (P &amp;lt; 0.01) from 90 days to 143 days. H&amp;E analysis revealed that the majority of tumors in all groups were high grade and that mice with ATRX loss were more likely to develop low grade tumors though this trend did not reach significance (P = 0.075). Expression of Ki67, GFAP and Olig2 was present in all groups, as shown by Immunophenotypic analysis. RNAseq analysis of murine tumor tissue revealed that ATRX loss in the context of G34R led to significant differential expression of 113 genes (78 upregulated and 35 downregulated) including upregulation of PRC2 target genes including HoxA genes. These findings highlight the cooperation between ATRX loss and H3.3G34R in gliomagenesis. Citation Format: Aalaa Abdallah, Herminio J. Cardona, David J. Picketts, Daniel J. Brat, Xiao-Nan Li, Oren J. Becher. A novel genetically engineered H3.3G34R model reveals cooperation with ATRX loss in upregulation of PRC2 target genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 912.
Abstract 3961: Cancer stem cells, not bulk tumor cells, predict mechanisms of resistance to SMO inhibitors in SHH medulloblastoma
Authors: Joshy George, Yaohui Chen, Nourhan Abdelfattah, Keiko Yamamoto, Scott Adamson, Jong Min Choi, Brad Rybinski, Anuj Srivastava, Parveen Kumar, Min Gyu Lee, David S. Baskin, Wen Jiang, Betty Y. Kim, William Flavahan, Jeffrey H. Chuang, Sung Yun Jung, Kyuson Yun
Journal: Cancer Research (2022)

Abstract The emergence of primary and acquired treatment resistance significantly reduces the clinical utility of many effective targeted therapies. Both genetic and epigenetic mechanisms of drug resistance have been reported in literature; however, whether these mechanisms are stochastically selected in individual tumors or governed by a predictable underlying principle is unknown.Here, we report that one can predict a priori the resistance mechanism that will arise in individual SMO inhibitor (SMOi)-resistant SHH medulloblastoma (MB), based on different CSC phenotypes in each tumor. We show that the dependence of cancer stem cells (CSCs), not bulk tumor cells, on the targeted pathway (sonic hedgehog (SHH) pathway) determines the molecular mechanism of resistance in individual tumors. Using both spontaneous (Fsmo;GFAP-cre) and transplantable (Ptch+/-;p53) mouse models of SHH MB treated with a Smoothened inhibitor, sonidegib/LDE225, we show that genetic-based resistance occurs only when the CSCs depend on the targeted pathway. In contrast, SHH MBs containing SHH-dependent bulk tumor cells but SHH-independent CSCs (SI-CSCs), acquire resistance through epigenetic reprogramming. Mechanistically, we discovered that the elevated proteasome activity in SMOi-resistant SI-CSC MBs alters the tumor cell maturation trajectory through enhanced degradation of specific epigenetic regulators, including the histone acetylation machinery. Consequently, SMOi-resistant SI- SMOi-resistant SI-CSC exhibit a global reduction of H3K9Ac, H3K14Ac, H3K56Ac, H4K5Ac, and H4K8Ac marks and gene expression changes. These results provide new insights into how selective pressure on distinct tumor cell populations contributes to different mechanisms of resistance to targeted therapies and implicate histone acetylation in the process. This information can be clinically exploited to understand responses and resistance to SMOis and other targeted therapies. Citation Format: Joshy George, Yaohui Chen, Nourhan Abdelfattah, Keiko Yamamoto, Scott Adamson, Jong Min Choi, Brad Rybinski, Anuj Srivastava, Parveen Kumar, Min Gyu Lee, David S. Baskin, Wen Jiang, Betty Y. Kim, William Flavahan, Jeffrey H. Chuang, Sung Yun Jung, Kyuson Yun. Cancer stem cells, not bulk tumor cells, predict mechanisms of resistance to SMO inhibitors in SHH medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3961.
Abstract 5462: BPI-361175, a 4th generation EGFR-TKI for the treatment of non-small cell lung cancer (NSCLC)
Authors: Lijia Liu, Changyong Qiu, Xiangyong Liu, Yuanyan Lian, Haibo Chen, Xiaodong Song, Qichao Shen, Guolong Du, Jing Guo, Dan Yan, Hong Lan, Lieming Ding, Jiabing Wang
Journal: Cancer Research (2022)

Abstract EGFR-activating mutations (Del19 or L858R) are major drivers in NSCLC (~40% in Asian and 10-20% in non-Asian). EGFR-TKIs have brought benefit to NSCLC patients with EGFR mutations, prolonging PFS and increasing quantity of life. Nevertheless, resistance inevitably emerges and leads to disease progression. Acquired EGFR C797S mutation is the most common event underlying resistance to the 3rd generation EGFR-TKIs, and there are no therapies. Herein, we report the discovery of BPI-361175, a 4th generation EGFR-TKI that overcomes EGFR resistant mutations. In vitro, BPI-361175 potently inhibited the activity of a variety of EGFR kinases, including triple (EGFRdel19 or L858R/T790M/C797S), double (EGFRdel19 or L858R/T790M, EGFRdel19 or L858R/C797S) and single (EGFRdel19 or L858R) mutations. Accordingly, BPI-361175 dose-dependently inhibited the phosphorylation of EGFR and the proliferation of cell lines harboring the above-mentioned mutations. Meanwhile, BPI-361175 were not active towards EGFRWT and IGF1R, therefore displayed good selectivity, both in kinase assays and in cell-based assays. In vivo, oral administration of BPI-361175 led to tumor suppression and regression in multiple EGFR mutant models, such as BaF3 EGFRDel19 or L858R/T790M/C797S, BaF3 EGFRDel19/C797S allograft models, and PC9 EGFRDel19/T790M/C797S, NCI-H1975 EGFRDel19/T790M/C797S, NCI-H1975 (EGFRL858R/T790M), HCC827 (EGFRDel19) CDX models, as well as a LDI-0025-200717 (EGFRDel19/T790M/C797S) PDX model. Remarkably, BPI-361175 significantly prolonged the life span of brain orthotropic BaF3 EGFRDel19/T790M/C797S allograft mice, demonstrating activity towards brain metastasis. In conclusion, BPI-361175 is a potent, selective, and orally bioavailable 4th generation EGFR-TKI which can potentially be used to treat NSCLC resistant mutations as well as at front line. Phase I clinical trial of BPI-361175 is enrolling patients in China, and US Phase I trial is expected to initiate in Q1 2022. Citation Format: Lijia Liu, Changyong Qiu, Xiangyong Liu, Yuanyan Lian, Haibo Chen, Xiaodong Song, Qichao Shen, Guolong Du, Jing Guo, Dan Yan, Hong Lan, Lieming Ding, Jiabing Wang. BPI-361175, a 4th generation EGFR-TKI for the treatment of non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5462.
Abstract 2976: Associate Professor
Authors: Fang Hua, Wenzhuo Hao, Lingyan Wang, Shitao Li
Journal: Cancer Research (2022)

Abstract Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that instigates several signaling cascades, including NF-κB signaling pathway, to induce cell differentiation and proliferation. Overexpression and mutations of EGFR are found in up to 30% of solid tumors and correlate with a poor prognosis. Although it is known that EGFR-mediated NF-κB activation is involved in tumor development, the signaling axis is not well elucidated. Here, we found that plakophilin 2 (PKP2) and the linear ubiquitin chain assembly complex (LUBAC) were required for EGFR-mediated NF-κB activation. Upon EGF stimulation, EGFR recruited PKP2 to the plasma membrane, and PKP2 bridged HOIP, the catalytic E3 ubiquitin ligase in the LUBAC, to the EGFR complex. The recruitment activated the LUBAC complex and the linear ubiquitination of NEMO, leading to IκB phosphorylation and subsequent NF-κB activation. Furthermore, EGF-induced linear ubiquitination was critical for tumor cell proliferation and tumor development. Knockout of HOIP impaired EGF-induced NF-κB activity and reduced cell proliferation. HOIP knockout also abrogated the growth of A431 epidermal xenograft tumors in nude mice by more than 70%. More importantly, the HOIP inhibitor, HOIPIN-8, inhibited EGFR-mediated NF-κB activation and cell proliferation of A431, MCF-7, and MDA-MB-231 cancer cells. Overall, our study reveals a novel linear ubiquitination signaling axis of EGFR, and perturbation of HOIP E3 ubiquitin ligase activity is potential targeted cancer therapy. Citation Format: Fang Hua, Wenzhuo Hao, Lingyan Wang, Shitao Li. Associate Professor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2976.